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Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR agonist (EC(50) = 4 nM, Eff = 149%). Oral administration of 6m to LDLR(-/-) mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.

The farnesoid X receptor (FXR; NR1H4) is an intracellular bile acid-sensing transcription factor that plays a critical role in the regulation of synthesis and transport of bile acids as well as lipid metabolism. Although the reciprocal relationship between bile acid and triglyceride levels is well known, the mechanism underlying this link is not clearly defined. In this study, we demonstrate that FXR regulates the expression of at least two secreted factors, complement component C3 and FGF15, the rat ortholog of FGF19, known to influence lipid metabolism. The analysis of the human complement C3 gene reveals the presence of functional FXR response elements in the proximal promoter of C3. Furthermore, rats given a single dose of an FXR agonist exhibit an increase in the plasma concentration of complement C3 protein. These studies demonstrate a mechanism by which FXR, a nuclear receptor with a limited tissue expression pattern, regulates secretion of factors that ultimately can affect lipid metabolism in an endocrine or paracrine manner.

Aberrant expression of myosin isoforms in skeletal muscles from mice lacking the rev-erbA␣ orphan receptor gene. Am J Physiol Regul Integr Comp Physiol 288: R482-R490, 2005. First published September 16, 2004; doi:10.1152/ajpregu.00690.2003.-The rev-erbA␣ orphan protein belongs to the steroid nuclear receptor superfamily. No ligand has been identified for this protein, and little is known of its function in development or physiology. In this study, we focus on 1) the distribution of the rev-erbA␣ protein in adult fast-and slow-twitch skeletal muscles and muscle fibers and 2) how the rev-erbA␣ protein influences myosin heavy chain (MyHC) isoform expression in mice heterozygous (ϩ/Ϫ) and homozygous (Ϫ/Ϫ) for a rev-erbA␣ protein null allele. In the fast-twitch extensor digitorum longus muscle, rev-erbA␣ protein expression was linked to muscle fiber type; however, MyHC isoform expression did not differ between wild-type, ϩ/Ϫ, or Ϫ/Ϫ mice. In the slow-twitch soleus muscle, the link between rev-erbA␣ protein and MyHC isoform expression was more complex than in the extensor digitorum longus. Here, a significantly higher relative amount of the ␤/slow (type I) MyHC isoform was observed in both rev-erbA␣ Ϫ/Ϫ and ϩ/Ϫ mice vs. that shown in wild-type controls. A role for the ratio of thyroid hormone receptor proteins ␣ 1 to ␣2 in modulating MyHC isoform expression can be ruled out because no differences were seen in MyHC isoform expression between thyroid hormone receptor ␣ 2-deficient mice (heterozygous and homozygous) and wild-type mice. Therefore, our data are compatible with the rev-erbA␣ protein playing an important role in the regulation of skeletal muscle MyHC isoform expression. orphan nuclear receptors; thyroid hormone; fast-and slow-twitch muscle THE VARIABLE EXPRESSION OF myofibrillar protein isoforms is a major determinant of the contractile properties and ATPase activities of skeletal and myocardial fibers (3, 50). The myosin heavy chain (MyHC) molecule is the most abundant myofibrillar protein and is encoded by a multigene family consisting of several members (35). Several isoforms have now been described in rodent skeletal muscles, including one slow isoform (type I or ␤/slow), three fast (IIa, IIx/d, and IIb), and two developmental (embryonic and neonatal/perinatal/fetal) isoforms, which are all coded by distinct genes (50). Four other MyHC isoforms, slow tonic, superfast IIm, ␣-cardiac-like, and extraocular myosin, are expressed in a few specialized muscles (7, 50). Despite their similarity in primary structure, the expression of different MyHC isoforms is precisely regulated in a tissue-specific and developmental stage-specific manner (50, 52). In addition, innervation patterns (33, 45, 46), altered physiological stimuli (34, 46), and various hormones (19) are known to have a significant impact on MyHC isoform expression.Skeletal muscle is a major target for hormone action. Thyroid hormone is one of the most potent regulators of skeletal muscle MyHC isoform expression in mammals, and it has been suggested...

Rodent motor units, muscle fibers, and motor proteins undergo significant aging-related changes. Such changes include spatial organization and physiological properties of fast- and slow-twitch single motor units, regulation of contractile speed and force generation capacity at the muscle fiber level, and altered functional properties of the motor protein myosin. In addition to specific changes, there also appears to be a "disorganization" of the coordinated expression of contractile, sarcoplasmic reticular, and mitochondrial protein isoforms in aging skeletal muscle. This is suggested to have a strong impact on aging-related impairments in muscle function in addition to the changes in specific muscle proteins.